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GLOBAL STANDARD OPERATING PROCEDURENumber
GSOP-011-005
Division: GLOBAL QUALITYPage
1 of 20
Revision
1
Title: ANNUAL PRODUCT QUALITY REVIEWS
1.0 Purpose
1.1 To establish a harmonized procedure for conducting Annual Product Quality Reviews of all
pharmaceutical products per the applicable regulatory requirements.
2.0 Scope
2.1 This Global SOP applies to the Apotex group of companies producing finished dosage forms, as
applicable to companys operation(s).
2.2 This Global SOP may be used for the assessment and oversight of Apotex Third Party Organizations.
2.3 This Global SOP establishes what shall be achieved by all parties planning for and carrying out Annual
Product Reviews in compliance with the regulatory requirements.
2.4 In some cases this Global SOP may address regulations and/or activities that do not apply to the
Site/Centralized Functional area operations. Each Site/Centralized Function shall justify non-applicability
during assessment and implementation of this Global SOP.
2.5 Where needed and justified, a Site/Centralized Function may create/revise a site-specific/centralized
function SOP on the subject of this Global SOP. The site-specific/centralized function SOP must not
contradict the requirements in this Global SOP and shall fulfill the requirements of this Global SOP, as
applicable to site/centralized function operations.
3.0 Owner Organizational Unit
AGO-QA-Global Policy and Systems
4.0 General Training Requirements
4.1 The following individuals of all Global, Corporate and Centralized functional areas (Quality, Compliance,
Legal, Drug Safety and Pharmacovigilance, Manufacturing Operations, Research and Development,
Engineering Services, Product Development and Technical Operations, Warehouse and Distribution and
Finance, etc.) must be trained on this Global SOP:
- Executive Management and members of the EOC
- Directors
- Senior Managers
4.2 Site Quality Heads must be trained on this Global SOP, if applicable to Site Operations.
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Title: ANNUAL PRODUCT QUALITY REVIEWS
4.3 Training of other Site/Centralized function personnel on the applicable requirements of this Global SOP
shall take place during site implementation of this Global SOP. This training will be executed on the
Site/Centralized function level SOP(s).
5.0 Associated Documents
Document # Document Title Relationship
GQM Global Quality Manual Governing Quality Manual
GPOL-002 Management Controls Governance,
Management Notification, Management
Review
Associated Global Policy
GPOL-007 Manufacturing, Packaging and Labelling
Controls
Associated Global Policy
GPOL-009 GMP Document Controls and Records
Management
Associated Global Policy
GPOL-011 Regulatory Program Associated Global Policy
GPOL-014 Quality Risk Management Associated Global Policy
GPOL-017 Failure and Deviation Investigation
Management
Associated Global Policy
GPOL-021 Corrective and Preventive Action (CAPA) Associated Global Policy
GSOP-026-002 Product Recall and Market Action Associated Global Standard
Operating Procedure
GSOP-026-003 Regulatory Notification Associated Global Standard
Operating Procedure
6.0 Exhibits
Exhibit Title
Exhibit A Annual Product Quality Review Process Overview
Exhibit B Annual Product Quality Review Relationship to the Quality System
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7.0 Definitions
Term Definition
Apotex Apotex group of companies producing finished dosage forms. Term also
includes the affiliates and distribution centers.
Corrective and Preventive
Action
A systematic approach that includes actions needed to correct (correction), avoid
recurrence (corrective action) and eliminate the cause of potential
nonconforming product and other quality problems (preventive action).
Out-of-Specification (OOS) Any examination, measurement or test value that does not conform to pre-
established criteria.
Out-of-Trend (OOT) Any analytical result that is within specification but is inconsistent with previously
determined results for the same material or similar results for similar materials.
For example, an in-specification result that is atypical outside the control limits
for the test.
Risk Assessment Determination of criticality based upon consideration of, but not limited to, the
following factors:
1. Compliance (QA/RA) Impact regulatory implications
2. Safety Risk (PV) risk to human life (considering severity, occurrences, etc.)
3. Distribution Pattern location of affected batches
4. Speed to initiate action
Third Party Manufacturer A universal term applied to a company under contract to manufacture products
distributed by Apotex. This would include the following:
- Contract Manufacturer/Packager a company under contract to manufacture
and/or package Apotex-owned products.
- Private Label Manufacturer a company who manufactures their products for
Apotex with an Apotex label.
- Joint Venture Manufacturer a company, who manufactures products for
Apotex that is jointly developed, owned and or marketed with Apotex.
Third Party Contractor
(TPC)
Any external entity manufacturing active pharmaceutical ingredient (API), bulk or
finished Apotex products.
- Any external entity responsible for packaging or repackaging bulk or finished
products (e.g. packagers, warehouses, distributors)
- Any contract analysis organization (including laboratory involved in testing of
APIs, API starting materials, bulk and finished Apotex products, development of
analytical testing methods, local retesting and execution of follow-up stability
studies)
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8.0 Process Overview
See Process Overview in Exhibit A.
9.0 Roles and Responsibilities
Role Responsibility
EVP,
Global Supply Operations
- Review and Approve this Global SOP
- Ensure the Deployment / Implementation of this Global SOP at
applicable Global Apotex sites
Executive Vice President,
Global R&D
- Review and Approve this Global SOP
- Ensure the Deployment / Implementation of this Global SOP within
Global R&D functions
Senior VP,
Scientific & Regulatory Affairs
- Review and approve this Global SOP
- Ensure the Deployment / Implementation of this Global SOP within
Scientific & Regulatory Affairs functions
Global Director,
R&D QA
- Review this Global SOP
- Ensure the Deployment / Implementation of this Global SOP within
R&D QA functions
Global Director,
External Quality
- Review this Global SOP
Global Director,
QA Audit
- Review this Global SOP
VP,
Global Quality Manufacturing
Sites
- Review this Global SOP
- Ensure the Deployment / Implementation of this Global SOP at
applicable Manufacturing sites
Global Director,
Quality Compliance
- Review this Global SOP
- Ensure the Deployment / Implementation of this Global SOP within
Global Compliance functions
Global Director, QA Policy and
Systems- Review and Approve this Global SOP
- Oversee the Management, Review, Approval, and Deployment /
Implementation of this Global SOP at applicable Global Apotex sites
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Role Responsibility
QA Global Policy and Systems
Department- Issue, review and revise this Global SOP according to current Health
Authority regulation and guidance
- Distribute this Global SOP
- Orchestrate the Deployment / Implementation of this Global SOP at
applicable Global Apotex sites
Site Leadership Team
(Site Operations Head,
Site Quality Head)
- Support Deployment / Implementation of this Global SOP at applicable
Global Apotex sites
- Coordinate Annual Product Quality Review activities across
interdisciplinary teams and departments at the site
- Ensure that Annual Product Quality Review processes are defined,
deployed and reviewed, and that adequate resources are available at
the site
10.0 General Requirements US Market
10.1 Apotex shall ensure that written records are maintained so that data therein can be used for evaluating,
annually (at minimum), the quality standards of each drug product to determine the need for changes in
drug product specifications, manufacturing or control procedures [CFR 211.180(e)]. This written
procedure establishes the process for such evaluations including provisions for:
- A review of a representative number of batches, whether approved or rejected and, where applicable,
records associated with the batch.
- A review of complaints recalls and returned drug products, and investigations conducted under CFR
211.192 for each drug product.
11.0 General Requirements - Health Canada
11.1 Regular periodic or rolling quality reviews of all drugs should be conducted with the objective of verifying
the consistency of the existing process, the appropriateness of current specifications for both raw
materials and finished product to highlight any trends and to identify product and process improvements.
Such reviews should normally be conducted and documented annually, taking into account previous
reviews, and should include, at minimum, a review of:
- Critical in-process controls, finished product testing results and specifications.
- All batches that failed to meet established specification(s) and their investigation.
- All significant deviations or non-conformances, their related investigations, and the effectiveness of
resultant Corrective and Preventive Actions (CAPA) taken.
- All changes carried out to the processes, analytical methods, raw materials, packaging materials, or
critical suppliers.
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- The results of the continuing stability program and any adverse trends.
- All quality-related returns, complaints and recalls and the investigations performed at the time.
- Adequacy of any previous corrective actions related to product process, or equipment.
- The qualification status of relevant equipment and systems (e.g. HVAC, water, compressed gases,
etc.); and
- Agreements to ensure that they are up to date.
Note: Quality reviews may be grouped by product type (e.g. solid dosage forms, liquid
dosage forms, sterile products, etc. where scientifically justified).
11.2 The Quality Assurance/ Control department of the importer or distributor should ensure that the annual
product quality review is performed in a timely manner.
11.3 Where required, there should be an agreement in place between the various parties involved (e.g.
importer and fabricator) that defines their respective responsibilities in producing and assessing the
Quality review and taking any subsequent CAPAs.
11.4 The Quality Assurance/Control department should evaluate the results of this review and an assessment
should be made whether CAPAs or any revalidation should be undertaken. Reasons for such corrective
actions should be documented. Agreed upon CAPAs should be completed in a timely and effective
manner. There should be procedures for the ongoing management and review of these actions and the
effectiveness of these procedures verified during self-inspection.
12.0 General Requirements European Market and PIC/s Countries
12.1 Apotex shall ensure that regular periodic or rolling quality reviews of all licensed medicinal products,
including export only products, are conducted with the objective of verifying the consistency of the
existing process, the appropriateness of current specifications for both starting materials and finished
product. Such reviews shall normally be conducted and documented annually taking into account
previous reviews, and shall include, at minimum, a review of:
- Starting materials and packaging material used for the product especially those from new sources.
- Critical in-process controls and finished product results.
- All batches that failed to meet established specification and their investigations.
- All significant deviations or non-conformances, their related investigations, and the effectiveness of
resultant CAPAs taken.
- All changes carried out to the process or analytical methods.
- Marketing Authorization variations submitted / granted / refused.
- The results of the stability monitoring program and any adverse trends.
- All quality related returns, complaints, recalls and investigations performed at the time.
- Adequacy of any other previous product process or equipment corrective actions.
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- Post-marketing commitments for new marketing authorizations and variations to marketing
authorizations.
- The qualification status of relevant equipment and utilities (e.g. HVAC, water, compressed gases
etc.).
- Technical Agreements to ensure that they are up to date.
12.2 The manufacturer and marketing authorization holder, where different shall evaluate the results of this
review and an assessment shall be made whether CAPA(s) or any revalidation shall be undertaken.
12.2.1 Reasons for such corrective actions shall be documented.
12.2.2 CAPAs shall be completed in a timely and effective manner. There shall be management
procedures for on-going management and review of these actions and the effectiveness of
these procedures verified during self-inspections. Product Reviews may be grouped by product
type (e.g. solid dosage forms, liquid dosage forms, sterile product, etc.) where scientifically
justified.
12.3 Where the marketing authorization holder is not the manufacturer, there shall be a Technical Agreement
in place between the various parties that defines their respective responsibilities in producing the product
quality review. The Qualified Person responsible for final batch certification together with the marketing
authorization holder shall ensure that the product review is performed in a timely and accurate manner.
13.0 Apotex Third Party Department Responsibilities:
13.1 In coordination with the Third Party Manufacturer), determine schedule of APR/PQR quality review
annually and communicate the schedule to the appropriate contractors / Apotex groups.
13.2 Receive and review the reports as provided from the Third Party Manufacturer sites and require any
necessary changes / corrections / additional information.
13.3 Work closely with the Data Contributors, responsible to prepare the sections not submitted by the Third
Party Manufacturer; assure that the format and content of the sections are as required in order to
complete the report. These may include sections such as Stability Assessment, Regulatory Assessment,
Technical Complaints, Medical Assessments, etc.
13.4 Collect, review and analyze data elements to provide an assessment of the process / product and make
recommendations for continuous improvement.
13.5 Review and approve the final report within the established timeframes.
13.6 Communicate overdue reports (or soon to be overdue reports) to Apotex-Management.
13.7 Provide risk assessment when required for product that is to be released during the time that the
APR/PQR review is overdue. Strong rationale must be provided to the Vice President, Global Quality and
Compliance.
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13.8 Ensure CAPAs defined in the outcome of the APR/PQR review are implemented at the Third Party
Manufacturer or by Apotex as appropriate. CAPA should be recorded and tracked.
13.9 Monitor implementation of the CAPAs defined in outcome of the APR/PQR and evaluate the effectiveness
of CAPA in the next annual review period.
13.10 Archive the final approved report in accordance with the local record retention requirements and the
related procedures
14.0 Annual Product Quality Review Responsibilities
14.1 Any Apotex site supplying intermediate or bulk product to another site must perform an annual scheduled
review of the supplied product.
14.2 The site filling the primary containers used for marketing must perform a product review. It must use the
results of any intermediate or bulk product supplying site review as part of the product review for which it
is responsible.
14.3 Sites or companies that carry out secondary packaging of filled primary containers, or import finished
products, must review the conformance of supplying site data to local market regulations.
14.4 Site Quality Head is responsible for:
- Overall coordination of Annual Product Quality Review and shall identify a representative(s) from the
Quality Assurance (QA) group for overall scheduling and management.
- Ensuring that the Annual Product Quality Review is completed on time.
- Overseeing the applicable processes listed in the SOP.
- Ensuring investigations when adverse trends are observed during the Annual Product Quality
Reviews.
- Reviewing and Approving the Annual Product Quality Review Summary Report:
Ensures a change record is created and agreeing with the recommended change(s).
Ensuring commitments for changes and improvements are tracked and completed
through the CAPA system.
14.5 Operations, Technical Services and QA are responsible for:
- Batch Record Review including In-process controls
- Review of Rework, reprocessing, and reject information
- Review of yields, deviations and product investigations
- Process Validation Review
- Product / Process related changes
- Effectiveness of Corrective Actions (close outs)
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- Follow-up from previous Annual Product Quality Review reports
- Significant product related deviations and incidents
14.6 Quality Control Laboratory and QA Heads are responsible for:
- Review of Quality Control Test results including out-of-specification events, non-conformances and
associated Laboratory Investigation Reports (LIR)
- Finished product specification review and change history
- Changes to Analytical Methods and Test Method Validation
- Stability Data and program review
- Retention Sample program review
15.0 Product Grouping Strategy (Except for US Products)
15.1 With the exception of the US products, grouping products by a particular characteristic/type is acceptable.
The grouping strategy must be applied with caution and using the following justification criteria examples:
- Common dose forms (sterile products, orals solutions, solid dosage, oral powders etc.)
- Common container closure formats different container sizes may be grouped (e.g. 20 mL and 25
mL of the same presentation).
- Different strength may be grouped if they are in the same container closure system
(e.g. 50 mg/100 mL and 100 mg/100 mL).
- Common APIs within a dose form.
- Products with substantially equivalent processing steps.
- Products with substantially equivalent excipient/carrier bases (e.g. oily versus aqueous preparations).
- Note: Products with different market authorization shall not be grouped together (e.g. OTC and
prescription) Grouping shall be justified in writing with the criteria used.
16.0 Scheduling
16.1 The periodic quality review for all Apotex products is to be performed annually based on a twelve month
review period. The responsible QA/APR/PQR Manager will generate the annual product review schedule
by the first of November of each year for the following calendar year.
16.2 All parties will mutually agree to an APR/PQR review reporting schedule by the end of November. The
schedule must include a timeline that allows for the completion of the review process so that it is not
longer than 90 days past the end of the 12 month data review period for Apotex products or not longer
than 120 days past the end of the 12 month data review period for Third Party manufactured products.
Typically, 30 days prior to the APR/PQR due date should be reserved to obtain approvals.
16.3 The agreed upon annual product quality schedule will be submitted to QA for formal approval.
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16.4 The approved product review schedule is a GMP document and should be maintained in the local
document management system with a requirement for retention as defined by global document retention
procedure.
16.5 Periodic status reports will be submitted to the appropriate site management team detailing the
compliance to the annual process.
17.0 Procedure
Note: Refer to Exhibit B for establishment of the relationship between the Annual Product Quality Review and
the Quality System.
17.1 An Annual Product Quality Review shall be compiled based on the approval date of the product. The
approved Annual Product Quality Review shall be available within 90 business days after the end of the
review period.
17.2 A cross-functional team based approach shall be used. While the overall coordination and preparation of
the Annual Product Quality Review dossier will reside with Site Quality Head, the individual section
preparation must be completed by the Subject Matter Experts in the respective departments as defined in
the responsibilities section of this procedure.
17.3 All batches of all the commercial products manufactured, packed and distributed during the review period
shall be included in the evaluation.
17.4 Along with the Annual Product Quality Review, implementation of previous years recommendations shall
be reviewed.
17.5 Site Quality Head or designee shall arrange a meeting with the concerned Department Heads to finalize
the action plan, responsibilities and deliverables (if any), based on the recommendations made in the
Conclusion section of the Annual Product Quality Review.
17.6 Site Quality Head or authorized designee shall approve the Annual Product Quality Review.
17.7 Details of any CAPAs (as required), shall be forwarded to the concerned Department Heads for
necessary actions.
17.8 Manager, QA or designee shall follow-up on the corrective action to ensure compliance of the comments /
recommendations.
17.9 The complete and approved Annual Product Quality Review shall be maintained by Quality Assurance as
per the retention period specified within applicable Global Policy [GPOL-009 - GMP Document Controls
and Records Management] and site procedures.
17.10 For products distributed in Europe, an electronic copy of the approved Annual Product Quality Review
(preferably in .pdf format) shall be shared with the Qualified Person at Apotex Netherlands within 30
business days from completion.
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17.11 Products that are discontinued will be periodically reviewed through the expiration date of the last batch
manufactured or the end of the stability study, whichever is longer.
18.0 Annual Product Quality Reviews Report Format
18.1 The Annual Product Quality Review report package must include (at minimum) the following information
and sections:
- Cover Page: Including Name of the product, Strength, Review Period, Market and Manufacturing
site.
- Summary Section
- Table of Contents
- Executive Summary Report: This shall include a section by section summary of the entire review,
along with a synopsis of any comments or concerns made in the individual section. It shall also
include a conclusion and rating identifying the corresponding action (Refer to Table 1).
Table 1: Conclusion Rating and Action
Rating Action
Acceptable No Risk assessment is warranted.
Acceptable with conditions Risk assessment shall be performed.
Unacceptable A risk assessment is warranted, and notification to
Regulatory Agencies shall be considered as a part of
mitigation and communication.
18.1.1 Batch Record Review
18.1.1.1 This section covers the results of the batch record review and a list of Batches
Released for commercial distribution, rejected / failed batches that failed to meet
established specifications.
18.1.1.2 Confirm that all batch records for commercial product have been reviewed as per the
Disposition process, including all batch records for rejected batches.
18.1.1.3 Where information is available via validated ERP system, batch disposition can be
retrieved electronically.
18.1.2 Starting Material and API Reviews
18.1.2.1 This section includes the review of API, excipients and primary packaging materials
used in the product. Also includes the API batches released and rejected / failed
during the review period. Trend analysis of API, excipients and primary packing
materials shall be part of this section as well as any changes to the suppliers.
18.1.3 Process Control Review
18.1.3.1 This section covers the review of critical in-process controls (In-process and finished
product acceptable quality levels). The results obtained shall be compared with the
standard values / range. For each batch, compile the percentage yield obtained at all
critical stages.
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18.1.4 Laboratory Test Results and Trends
18.1.4.1 This section evaluates the analytical test results of finished products and in-process
data of all relevant critical parameters including trend analysis of these critical
parameters.
18.1.5 Laboratory Out-of-Specification (OOS) and CAPA
18.1.5.1 This section summarizes all deviations, incidents, notifications, OOS, Out-of-Trend
(OOT), LIR, AQRS (CAPA, Investigation and Excursion) and related detailed
investigations including the effectiveness of CAPAs executed.
18.1.6 Change Control Review
18.1.6.1 This section covers the summary of any changes carried out to the product, process
(manufacturing, packaging, labelling and specification), system or methods specific to
the product.
18.1.7 Validation Review
18.1.7.1 This section summarizes the validation study details of manufacturing process
(completed and on-going process validation studies).
18.1.8 Facilities and Equipment Review (Product Specific)
18.1.8.1 This section reviews the qualification status of equipment and utilities (e.g. HVAC,
Water, compressed air etc.). This section also covers the review of the Qualification
status of new / existing and re-qualification of the equipment and utilities.
18.1.9 Specifications Review
Note: This section is applicable only to the sites that do not have established regular
Compendia review program.
18.1.9.1 Material and Product Specification Review
18.1.9.1.1 This section covers the review of current specifications (API, In-process,
stability and finished product) to be in line with the approved
manufacturing documentation.
18.1.9.1.2 Summarize the results of the verification and highlight any gaps.
18.1.9.2 Compendia Specification Review
18.1.9.2.1 This section covers the review of current specifications (API, In-process,
stability and finished product) with respect to appropriate product
monograph.
18.1.9.2.2 Summarize the results of the verification and highlight any gaps.
18.1.10 Customer Complaints Review
18.1.10.1 This section summarizes the market complaint investigation and planned
CAPAs.
18.1.11 Medical Complaints (Adverse Events)
18.1.11.1 Drug Safety / Pharmacovigilance shall include in their assessment report input
on Adverse Events with possible technical background. This should be
available for the Apr/PQR technical writer.
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18.1.11.2 Manufacturing sites that include this information as part of their complaint trend
report do not need to include this within the APR/PQR, but must provide the
appropriate link to the information.
18.1.12 Regulatory Actions Review
18.1.12.1 This section covers the field alerts, product recalls and returned goods (if any).
Also includes, reasons and corrective actions planned.
18.1.13 Marketing Authorization Variations and Post-Marketing Commitments
18.1.13.1 Regulatory team shall provide a summary of the marketing authorization
variations submitted, granted, or refused during the reporting period, the filed
document reference, and post-marketing commitments for markets as
applicable, as per the local GMP requirements for those markets e.g. EU and
Aus require a summary of variations and commitments. Include the report as
an attachment to the APR/PQR.
18.1.14 Returned Products
18.1.14.1 Gather information for all returned products related to quality issues which
occurred during the review period; including the reason for return.
18.1.14.2 Using the table in the APR/PQR report, provide the following information:
- Type - Issue Category (Product Returned)
- Number of actions
- Associated batch numbers
- Trend (Yes/No)
- Comments and/or corrective actions taken
18.1.14.3 If investigations were initiated, the results and the decision on the final use
should also be listed.
18.1.14.4 Any products that were returned as a result of a customer complaint should
also be evaluated.
18.1.15 Technical Agreements
18.1.15.1 This section reviews the technical agreements between Apotex and the third
party manufacturer or contractor to ensure that they are up to date (as
applicable).
18.1.16 Retention Sample Program Review
18.1.16.1 This section covers the retention sample review of the product.
18.1.16.2 Sites shall have site specific SOP for the collection, storage, retrieval; review
and disposition of reserved/control samples for drug products with delineation
of retention period(s) and visual inspection requirements.
18.1.16.3 Visual inspection with the opening of the primary packaging shall be performed
at least once a year against visual appearance specifications.
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18.1.17 External Manufacturing / Testing Services Review
18.1.17.1 Review of the Third Party Manufacturers APQR (if any) and the comment /
suggestions will be included in this section. Comments / Suggestions (if any)
will be forwarded to the Third Party manufacturer by the External
Manufacturing Quality group.
18.1.18 Stability Program
18.1.18.1 This section covers the review of results of the stability monitoring program
including the available raw data for stability and references to full stability
reports.
18.1.19 Review of Previous Annual Product Quality Review
18.1.19.1 The Technical Writer or data contributor (as appropriate) will obtain a copy of
the previous APR/PQR.
18.1.19.2 The report will be reviewed to determine whether there were any actions and/or
recommendations that should be considered for the current review period. The
reviewer will determine the status of the recommended actions and include the
information pertaining to recommendations and status of actions in the relevant
section of the report.
18.1.20 Recommendations and Conclusions
18.1.20.1 Include any recommendations generated during the review and analysis of the
data. During the review process, any changes, additional information or
corrections will be communicated to the author of the section or to the Third
Party contractor or manufacturer as applicable. The holistic review will be
completed once all sections are deemed appropriate.
18.1.20.2 The authors are to provide specific statements (as applicable to their section)
on the compliance and validation status and include any new knowledge
gained during the review process and defining corrective actions to be taken to
remediate any issues observed.
18.1.20.3 The executive summary will be generated by QA following the holistic review
and will include the necessary detail to assess the current status of the product
with the recommendations as noted above for any areas of improvement or
concern.
18.1.20.4 The recommendations must include supporting evidence that will provide a
reference as to why the recommendation is necessary and why it is considered
to be appropriate. Any follow-up actions required for Apotex products
manufactured by or on behalf of Apotex will be coordinated and supervised by
the appropriate Quality Unit. For Third Party manufacturers, the Apotex Quality
unit responsible for the oversight of the product or manufacturer will
communicate the information to the third party manufacturer and provide
oversight of the follow-up measures.
18.1.20.5 Any critical issue identified should be escalated as per GPOL-002 -
Management Controls - Governance, Management Notification, and
Management Review.
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18.1.20.6 Quality Assurance will monitor and update the status of the follow-up activities
related and/or required from the APR/PQR review report. A compliance record
will be generated for recommendations (as appropriate) with any required
CAPAs produced as child records of the associated recommendation
compliance record. The status updates of the activities will be communicated
to the appropriate management group periodically (but not less than quarterly)
until they are completed.
18.1.21 Approvals Page
18.1.21.1 This section documents Reviewer and Approver signatures.
Note: Completed APR/PQR reports should be made available to Third Party
Customers who require the document as outline in Quality Agreements with
that customer.
19.0 Data Analysis and Trending
19.1 Appropriate statistical analysis must be applied to the review of relevant quality data.
19.2 Non-statistical analysis such as reviews of graphs shall be interpreted for the reviewer as to its
explanations and conclusion.
19.3 The data generated from the batch or product shall be trended using the appropriate statistical techniques
such as time series plots, control charts, etc to draw the conclusions, if any. This will help the
manufacturer to take any corrective or preventive action, should manufacturer find the process to be out
of control.
19.4 The data should be trended and analyzed to determine if (i) if the process is in control, (ii) whether the
process continues to be in validated state and (iii) if any improvements are indicated based on process
trends.
19.5 Appropriate graphical and statistical tools and methodologies shall be applied to demonstrate valid
quantitative and qualitative interpretations. Such tools and methodologies may include, statistical control
charting, and process capability studies.
19.6 Statistical analysis must be conducted and interpreted by qualified individuals.
20.0 System Monitoring
20.1 Key Performance Indicators (KPIs) of the APR/PQR program, including on time completion, must be
established and monitored through monthly reporting with escalation as needed. Corrective actions must
be implemented if required by KPIs.
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21.0 Differences Between FDA and European Product Reviews
21.1 Refer to Table 2 for guidance when preparing two separate Annual Product Quality Reviews for different
Regulatory Agencies.
Table 2: Differences between FDA and European Product Reviews
Objective FDA EU / PIC/s / Canada
Determine appropriateness, or need to change, product
specifications
Required Required
Determine appropriateness, or need to change,
specification for starting materials
Not specified Required
Review the need to change manufacturing procedures Required Not specified
Review the need to change in-process controls Required Not specified
Verify consistency of existing process Not specified Required
Need for re-validation of processes Not specified Required
Highlight trends Expected Required
Identify product/process improvements Not specified Required
Identify corrective actions Expected Required
Consider previous reviews Expected Required
Grouping of products Not allowed Allowed
22.0 Risk Assessment and Revalidation Programs
22.1 Risk assessments must be conducted for all products where the final conclusion is Acceptable with
conditions or Unacceptable. The risk assessment must be conducted per appropriate tools described
in the Quality Risk Management Global Policy [GPOL-014] and Global SOP. The outputs of the risk
assessment shall include conclusions and recommendations for risk reduction, risk avoidance, or risk
mitigation. CAPA activities generated as a result of the risk assessment must be approved by Quality
Assurance. For all product reviews receiving an Unacceptable rating, Site and Corporate Quality and
Regulatory Management must be promptly notified as per the Management Control Global Policy [GPOL-
002].
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23.0 External References
Document Title Reference Type
Health Canada - C.02.011 Manufacturing Control, Section 51 Annual
Product Quality Review Section 51 55
(www.hc-sc.gc.ca)
Health Canada Regulation
Code of Federal Regulations, Title 21, Volume 4, Revised April 1, 2012
"Title 21, Food And Drugs, Chapter I-Food And Drug Administration,
Department Of Health And Human Services,
Subchapter C-Drugs: General
Part 211, Current Good Manufacturing Practice For Finished
Pharmaceuticals"
Subpart J, Records and Reports
Sec 211.180(e), General Requirements
Sec 211.192, Production Record Review
(www.fda.gov)
US FDA Regulation
EudraLex, The Rules Governing Medicinal Products in the European
Union, Volume 4, EU Guidelines for Good Manufacturing Practice for
Medicinal Products for Human and Veterinary Use
Part 1, Basic Requirements for Medicinal Product
Section 1 Quality Management Product Quality Review,
(www.ec.europa.eu)
European Commission
Guidance
(EMEA,MHRA)
Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-
Operation Scheme, Guide To Good Manufacturing Practice For
Medicinal Products, 15 January 2009
Chapter 1, Quality Management
Section 1.4, Product Quality Review
(www.picscheme.org)
PIC/S Guidance
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24.0 Revision History
Revision
No.
Effective
Date
Change
Control
No.
Description / Reason for ChangeAuthor of
Revision
1 Current 75529 1. Updated the 'Scope', General
Training Requirements and Roles and
Responsibilities sections of the
document to align with the current
GPOL/GSOP template.
2. Update Document references where
applicable for consistency with new
referenced document numbers and
titles.
3. Updated Regulatory Department
responsibilities; Update product
grouping strategy and exclude
salvaged product term for clarity.
4. Excluded redundant Specification
content comparison with the product
dossier requirement.
5. Updated additional sections
throughout the documents where
applicable as appropriate for
compliance and alignment with
established process.
Elaine Leong,
Manager, QA
Global Policy and
Standards
0 10/03/2013 52820 New Global Standard Operating
Procedure GSOP-011-005 Annual
Product Quality Reviews
Elaine Leong,
Manager, QA
Global Policy &
Standards
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Exhibit A: Annual Product Quality Review Process Overview
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Exhibit B: Annual Product Quality Review Relationship to the Quality System
APR
CAPA and
Improvement
Compliance to
license, and
applications
Validation,
Re-Validation
and VMP
Specifications
and Controls
Product Risk
Management
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APPROVALS AND SIGNATURES
UserName: Ross Maclean (apotexmaclean) Title: Senior VP, Scientific & Regulatory Aff Date: Thursday, 17 July 2014, 02:27 PM Eastern Time Meaning: Approval ================================================
UserName: Brian Magerkurth (apotex\bmagerku) Title: EVP, Global Supply Operations Date: Thursday, 17 July 2014, 02:34 PM Eastern Time Meaning: Approval ================================================
UserName: Pradeep Sanghvi (apotex\psanghvi) Title: Executive Vice President, Global R&D Date: Thursday, 17 July 2014, 07:47 PM Eastern Time Meaning: Approval ================================================
UserName: Victoria Chester (apotex\vchester) Title: Global Director, QA Policy and Systems Date: Friday, 18 July 2014, 12:38 AM Eastern Time Meaning: QA Approval ================================================
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